Activin A exerts its biological activities by binding to the type 2 serine/threonine kinase Activin RIIA which then noncovalently associates with the type 1 serine/threonine kinase Activin RIB/ALK-4 (7, 11). Signaling through this receptor complex leads to Smad activation and regulation of activin-responsive gene transcription (7, 11). The bioactivity of Activin A is regulated by a variety of mechanisms (11). BAMBI, Betaglycan, and Cripto are cell‑associated molecules that function as decoy receptors or limit the ability of Activin A to induce receptor complex assembly (12‑14). The intracellular formation of Activin A can be prevented by the incorporation of the beta A subunit into Activin AC or Inhibin A (3, 10). And the bioavailability of Activin A is restricted by its incorporation into inactive complexes with alpha 2-Macroglobulin, Follistatin, and FLRG (15, 16).
Activin A is involved in the differentiation of various cell
and tissue types. The induction of definitive endoderm by Activin A is required
in differentiation protocols of induced pluripotent stem cells (iPSCs) (17, 18).
In vitro models of human gametogenesis use prolonged Activin A supplementation
to human embryonic stem cells for differentiation into human primordial germ
cell-like cells (19). Activin A can also be used to maintain cells in vitro, as
is the case for iPSC-derived nephron cells that can then be used in disease
modeling, drug screening and in regenerative medicine (20).
Activin A is an
important factor for tumor cells to evade the immune system as Activin A can
act on surrounding immune cells to decrease their antitumor activity (21).
Activin A also promotes migration and growth of tumors, making it a target for
cancer therapies (22). Specifically, research has shown that interfering with
Activin A activity can assist in overcoming CD8 T-cell exclusion and
immunotherapy resistance (23). In bone marrow-derived stem cell transplants for
treatment of diabetes, Activin A enhances migration and homing of stem cells
towards pancreatic lineage (24).